脂肪来源干细胞衍生的外泌体通过递送 XIST 和恢复圆盘蛋白受体 2 促进皮肤伤口愈合。

Adipose-derived stem cells-derived exosomes facilitate cutaneous wound healing by delivering XIST and restoring discoidin domain receptor 2.

机构信息

Department of Plastic Surgery 18, Plastic Surgery Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100144, PR China.

Department of General Surgery, Xuzhou Hospital of Traditional Chinese Medicine, the Affiliated Xuzhou Hospital of Nanjing University of Chinese Medicine, Xuzhou 221000, Jiangsu, PR China.

出版信息

Cytokine. 2022 Oct;158:155981. doi: 10.1016/j.cyto.2022.155981. Epub 2022 Aug 8.

DOI:10.1016/j.cyto.2022.155981

PMID:35952595

Abstract

BACKGROUND

Adipose-derived stem cells (ADSCs) and their derived exosomes (ADSC-Exos) have shown potential functions in tissue repair. This study focuses on the effects of ADSCs-Exos on cutaneous wound healing and the potential involvement of the long non-coding RNA (lncRNA) XIST/microRNA-96-5p (miR-96-5p)/discoidin domain receptor 2 (DDR2) axis.

METHODS

Exos were isolated from the ADSCs and identified. A mouse model of full-thickness skin wounds was established. The mice were treated with ADSC-Exos to evaluate the function of ADSC-Exos in wound healing. Mouse dermal fibroblasts (MDFs) were co-cultured with the ADSC-Exos for in vitro experiments. The most differentially expressed lncRNAs in mouse skin tissues after ADSC-Exo treatment were screened by microarray analysis. The downstream molecules were analyzed by bioinformatics tools. Gain- and loss-of-function studies were performed to examine the functions of the XIST/miR-96-5p/DDR2 axis in wound healing.

RESULTS

ADSC-Exos facilitated wound healing in mice, reduced inflammatory infiltration, and increased collagen deposition in the wound skin tissues. In vitro, the ADSC-Exos promoted proliferation, migration of the MDFs. XIST was the most upregulated lncRNA in MDFs after ADSC-Exo treatment. Downregulation of XIST suppressed the promoting role of ADSC-Exos in wound healing. XIST bound to miR-96-5p to restore the expression of DDR2 mRNA. Either silencing of miR-96-5p or overexpression of DDR2 restored the promoting functions of ADSC-Exos in proliferation and migration of MDFs.

CONCLUSION

This study demonstrates that ADSC-Exos-carried XIST accelerates cutaneous wound healing through suppressing miR-96-5p and restoring the DDR2 expression.

摘要

背景

脂肪干细胞（ADSCs）及其衍生的外泌体（ADSC-Exos）在组织修复中显示出潜在的功能。本研究重点探讨 ADSC-Exos 对皮肤创伤愈合的影响，以及长链非编码 RNA（lncRNA）XIST/微小 RNA-96-5p（miR-96-5p）/盘状结构域受体 2（DDR2）轴的潜在参与。

方法

从 ADSCs 中分离外泌体并进行鉴定。建立全层皮肤创伤小鼠模型，用 ADSC-Exos 处理小鼠，评估 ADSC-Exos 在伤口愈合中的作用。将小鼠真皮成纤维细胞（MDFs）与 ADSC-Exos 共培养进行体外实验。通过微阵列分析筛选 ADSC-Exo 处理后小鼠皮肤组织中差异表达最明显的 lncRNA。利用生物信息学工具分析下游分子。通过增益和缺失功能研究检验 XIST/miR-96-5p/DDR2 轴在伤口愈合中的功能。

结果

ADSC-Exos 促进了小鼠伤口愈合，减少了伤口皮肤组织中的炎症浸润，增加了胶原蛋白沉积。体外实验中，ADSC-Exos 促进了 MDFs 的增殖和迁移。ADSC-Exo 处理后，MDFs 中上调最明显的 lncRNA 是 XIST。下调 XIST 抑制了 ADSC-Exos 对伤口愈合的促进作用。XIST 与 miR-96-5p 结合，恢复 DDR2 mRNA 的表达。沉默 miR-96-5p 或过表达 DDR2 均可恢复 ADSC-Exos 对 MDFs 增殖和迁移的促进作用。